The overall goal of this project is to assess cholinergic receptor density in Alzheimer's disease (AD) and mild cognitive impairment (MCI) using positron emission tomography (PET) imaging. AD causes enormous morbidity and is becoming a major healthcare problem among veterans as the population ages. Several distinct neuropathological events occur in AD. The relative contribution of each event to clinical symptoms and disease progression is unclear, and developing effective treatments based on known abnormal proteins and processes in AD has been elusive. Currently, there are few tools available to study neuropathology or disease expression in vivo. Altered cholinergic neurotransmission is a core neurobiological feature of AD. In recent years, AD research has focused largely on other cellular and molecular events, such as beta-amyloid production and deposition. Nonetheless, recent work continues to support a critical role for the cholinergic receptor system in AD - as a primary AD pathology, via interactions with neuropathological proteins such as beta-amyloid, or by mediating the expression of cognitive deficits. Recently, the PET ligand 2-18F-fluoro-3-(2(S)azetidinylmethoxy) pyridine (2-FA) was developed to measure regional nicotinic 1422 receptors (nAChR) in vivo. The improved technique is safe for use in humans, and is sensitive and reliable. There is limited experience with its use in AD, although preliminary studies by our group and others suggest that cortical nAChRs can be measured accurately in AD, and binding is reduced in AD and lower density may be associated with cognitive deficits. The proposed project uses 2-FA PET imaging to compare nAChR binding in AD patients and healthy older adults. Three related questions are addressed: 1) What is the extent of reduced nAChRs in AD? Are alterations present in those with MCI and at risk for progression to AD?, 2) Where in the brain are nAChRs abnormal in AD?, and 3) Are regional reductions in nAChR binding in AD associated with global cognitive impairment or with specific deficits in memory or attention? To answer these questions, patients with mild to moderate AD, those with amnestic MCI, and healthy older adults will undergo clinical assessment and 2-FA PET imaging. We will compare global and regional nAChR binding between the groups and examine the association between regional nAChR binding in whole brain, temporal cortex, and frontal cortex, and measures of global cognition, memory, and attention. The MCI group will be followed for two years and the relationship between baseline nAChR binding and subsequent change in cognition will be assessed. Results of this study can define the extent of reduced nAChRs in specific brain regions in AD and MCI in vivo and their contribution to global and distinct cognitive deficits. The study also advances 2-FA imaging as a biomarker for cholinergic dysfunction in AD and MCI that can be used in future studies to identify very early cholinergic changes in AD, measure change over time, evaluate associations with other AD neuropathologies, assess response to therapeutic interventions, and provide a target for new medication development